PortalPortal HypertensionHypertension andand itsits ComplicationsComplications

TomTom FrazierFrazier WhatWhat II’’mm GonnaGonna TellTell YouYou

„ Pathophysiology of Portal HTN and its Complications „ Review diagnostic concerns and management of… „ Ascites „ Gastric and esophageal varices „ HRS „ HPS „ Hepatic encephalopathy

J Physiol Pharmacol. 2008 Aug;59 Suppl 2:231-8 WhatWhat II expectexpect youyou toto rememberremember

„ GeneralGeneral PathophysPathophys ofof portalportal htnhtn,, he,he, varices,varices, hrshrs „ WhereWhere toto findfind answersanswers whenwhen theythey comecome upup „ HEHE treatmenttreatment andand problemsproblems withwith ourour curentcurent assumptionsassumptions PathogenesisPathogenesis ofof PortalPortal Hypertension:Hypertension: HemodynamicHemodynamic FactorsFactors

„ Cirrhosis most common etiology „ portal pressure gradient > 5 mm Hg „ Hallmark is a pathologic increase in the pressure gradient between the portal vein and the inferior vena cava, which is measured by the hepatic venous pressure gradient (HVPG) „ HVPG = WHVP – FHVP „ Ohm's law: P= Q (blood flow) x R „ Two steps „ Decreased outflow „ Increased inflow ClassificationClassification ofof portalportal hypertensionhypertension StepStep 1:1: IncreasedIncreased outflowoutflow resistanceresistance

„ ThisThis resultsresults fromfrom 22 factors:factors: „ (1)(1) mechanicalmechanical obstructionobstruction toto flowflow becausebecause ofof fibroticfibrotic disruptiondisruption ofof architecturearchitecture „ (2)(2) aa dynamicdynamic componentcomponent producedproduced byby activeactive contractioncontraction ofof vascularvascular smoothsmooth musclemuscle cellscells andand activatedactivated stellatestellate cellscells „ TheThe dynamicdynamic componentcomponent accountsaccounts forfor approximatelyapproximately 30%30% ofof thethe intrahepaticintrahepatic resistanceresistance inin cirrhosiscirrhosis StepStep 1:1: TheThe DYNAMICDYNAMIC componentcomponent

„ Intrahepatic ↓(eNOS) activity and NO production. „ impaired Akt-mediated eNOS phosphorylation (which is partially reversible by statins) „ increased caveolin expression (particularly if folate deficiency exists). „ nitrosylation reactions secondary to oxidative stress (↓NO) and vasoconstriction mediated by endothelin, angiotensinogen, and eicosanoids. „ other vasoactive mediators such as carbon monoxide, adrenergic tone, endotoxemia, and inflammatory cytokines StepStep 2:2: IncreasedIncreased PortalPortal VenousVenous InflowInflow

„ Mesenteric arterial vasodilation „ ↑ portal venous inflow „ systemic hyperdynamic circulatory state (↓ svr and map with ↑ CO). „ Caused by ↑ NO „ Shear stress, ↑ VEGF, and TNF-α are causes of ↑ splanchnic NO production in cirrhosis „ ↑ heme oxygenase activity and CO production may also contribute „ Bacteremia can ↑ vasodilation by stimulating TNF-α production and activation of endocannabinoids, which are potent vasodilators. „ Blockade of VEGF signaling attenuates the increase in portal venous inflow seen in cirrhosis PortalPortal HTNHTN andand itsits ComplicationsComplications

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Clinics in Liver Disease - Volume 9, Issue 4 (November 2005) AcitesAcites FormationFormation

„ IncreasedIncreased hepatichepatic sinusoidalsinusoidal pressurepressure „ ThreeThree interrelatedinterrelated pathophysiologicpathophysiologic processesprocesses contributecontribute toto thethe developmentdevelopment ofof ascites.ascites. „ systemicsystemic arteriolararteriolar vasodilation,vasodilation, „ activationactivation ofof NaNa andand H2OH2O retention,retention, „ sinusoidalsinusoidal portalportal hypertension.hypertensi